Ion channels and aquaporins are differentially expressed in retinal cells, and play important roles in ion and water movements that are crucial for adequate control of retinal hydration.
Among the isoforms of the AQP protein family identified so far, at least four AQPs are found to be expressed in the neural retina, AQP0, AQP1, AQP4 and AQP9. AQP0 is expressed in subpopulations of bipolar cells, amacrine cells and retinal ganglion cells (RGCs) (I. Iandiev, T. Pannicke, W. Härtig, J. Grosche, P. Wiedemann, A. Reichenbach and A. Bringmann, Localization of aquaporin-0 immunoreactivity in the rat retina, Neurosci. Lett. 426 (2007), pp. 81-86.). AQP1 is normally expressed in the outer retina in photoreceptors and in distinct amacrine cells (I. Iandiev, T. Pannicke, M. B. Reichel, P. Wiedemann, A. Reichenbach and A. Bringmann, Expression of aquaporin-1 immunoreactivity by photoreceptor cells in the mouse retina, Neurosci. Lett. 388 (2005), pp. 96-99.), whereas AQP4 is expressed predominantly in the perivascular and vitreal end feet of Müller cells and in astrocytes in the inner retina (M. J. Goodyear, S. G. Crewther and B. M. Junghans, A role for aquaporin-4 in fluid regulation in the inner retina, Vis. Neurosci. 26 (2009), pp. 159-165.).
It has been demonstrated that the alteration of amount and/or location of glial expression of AQP 4 mostly, but also of AQP1, in the retina leads to fluid accumulation in and/or under the retina. AQPs 1 and 4 were indeed found to be altered in a variety of animal model diseases, which include ischemia/reperfusion (I. Iandiev, T. Pannicke, B. Biedermann, P. Wiedemann, A. Reichenbach and A. Bringmann, Ischemia-reperfusion alters the immunolocalization of glial aquaporins in rat retina, Neurosci. Lett. 408 (2006), pp. 108-112.) and streptozotocin (STZ)-induced diabetes (I. Iandiev, T. Pannicke, B. Biedermann, A. Reichenbach, P. Wiedemann and A. Bringmann, Diabetes alters the localization of glial aquaporins in rat retina, Neurosci. Lett. 421 (2007), pp. 132-136.).
For example, after ischemia, retinal glial cells in the nerve fiber/ganglion cell layers strongly expressed AQP1 (I. Iandiev, T. Pannicke, B. Biedermann, P. Wiedemann, A. Reichenbach and A. Bringmann, Ischemia-reperfusion alters the immunolocalization of glial aquaporins in rat retina, Neurosci. Lett. 408 (2006), pp. 108-112.). Furthermore, the perivascular staining around the superficial vessels switched from AQP4 in control retinas to AQP1 in post-ischemic retinas (I. Iandiev, T. Pannicke, B. Biedermann, P. Wiedemann, A. Reichenbach and A. Bringmann, Ischemia-reperfusion alters the immunolocalization of glial aquaporins in rat retina, Neurosci. Lett. 408 (2006), pp. 108-112.). The data suggest that the glial cell-mediated water transport in the retina is altered after ischemia especially at the superficial vessel plexus.
With regards to diabetes, a microarray study demonstrated that AQP1 and AQP4 gene expression is up-regulated in the retinas of diabetic rats (I. Iandiev, T. Pannicke, B. Biedermann, A. Reichenbach, P. Wiedemann and A. Bringmann, Diabetes alters the localization of glial aquaporins in rat retina, Neurosci. Lett. 421 (2007), pp. 132-136.). Moreover, AQP1 immunoreactivity was enhanced in glial cells located in the innermost retinal layers and those surrounding the superficial vessels in STZ-induced diabetic rats. Perivascular AQP4 expression was reportedly reduced in the superficial vessel plexus but unaltered in the inner nuclear layer (INL) (I. Iandiev, T. Pannicke, B. Biedermann, A. Reichenbach, P. Wiedemann and A. Bringmann, Diabetes alters the localization of glial aquaporins in rat retina, Neurosci. Lett. 421 (2007), pp. 132-136.).
Furthermore, it has been shown that endotoxin-induced uveitis (EIU) in rats alters the expression of Kir4.1 and AQP4 in the retina (Liu X Q, Kobayashi H, Jin Z B, Wada A, Nao-I N. Differential expression of Kir4.1 and aquaporin 4 in the retina from endotoxin-induced uveitis rat. Mol Vis. 2007 1; 13:309-17.).
Retinal degeneration has been associated with a mislocation of Kir4.1 and loss of AQP4 expression. (Yuan S, Zhang W, Ding J, Yao J, Jiang Q, Hu G. Increased sensitivity to retinal light damage in aquaporin-4 knockout mice. Exp Eye Res. 2009; 89(1):119-22.) Finally, it was demonstrated that Müller glial cells respond to excessive light with an alteration in the localization of Kir4.1 and aquaporin-4 proteins; (Localization of glial aquaporin-4 and Kir4.1 in the light-injured murine retina. Iandiev I, Pannicke T, Hollborn M, Wiedemann P, Reichenbach A, Grimm C, Remé CE, Bringmann A. Neurosci Lett. 2008; 434(3):317-21.).
In summary, in all the models of retinal diseases, associated with fluid homeostasis de regulation, AQP4, AQP1 and Kir4.1 have been shown to be over or under expressed and mislocalized.
However, the molecular mechanisms regulating physiologic or pathologic hydro-ionic regulation in the retina remain unexplored.